1. Field of the Invention
This invention relates to novel furan nitrone compounds and their use as free radical trapping agents and therapeutic agents. More particularly, this invention concerns furan nitrone compounds and their use as analytical reagents for detecting free radicals and as therapeutics for treating various medical dysfunctions and diseases.
2. State of the Art
Nitrones, such as .alpha.-phenyl-N-tert-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), are known to be useful as analytical reagents for detecting free radicals. Such compounds function as "spin traps" by reacting with unstable free radicals to form relatively stable free radical spin adducts which are observable by electron spin resonance (ESR) spectroscopy. Thus, spin trapping allows previously unobservable free radicals to be identified and studied using ESR and related techniques.
The use of nitrones as spin traps for studying unstable free radicals has been applied to biological systems. In this regard, PBN, DMPO and related compounds have been used to identify superoxide (O.sub.2.sup.-.) and hydroxyl radicals (HO.) in biological systems. Additionally, such nitrones have been used to study lipid peroxidation and other free radical-induced biological processes.
More recently, nitrone compounds, such as PBN and derivatives thereof, have been reported as therapeutics for the treatment of a wide variety of disease conditions arising from or characterized by free radical-induced oxidative damage. Such disease conditions include, for example, disorders of the central nervous system (CNS) and the peripheral nervous system, such as stroke, Parkinsonism, traumatic nerve damage and the like, and disorders of the peripheral organs, such as atherosclerosis, cardiac infarction, ulcerative colitis and the like. Nitrones have also been reported to treat certain inflammatory conditions, such as arthritis.
Although various nitrone compounds have been previously reported to be useful as analytical reagents or therapeutic agents, a need exists for novel nitrone spin traps having improved effectiveness in these applications. For example, when using nitrones as therapeutic agents for treating acute conditions, such as stroke, cardiac infarction or the like, it is particularly desirable to be able to administer the nitrone spin trap at high doses, especially to the localized area immediately surrounding the acute incident, to minimize the amount of free radical-induced oxidative damage that occurs. Thus, nitrone compounds used to treat acute conditions should be non-toxic or have very low toxicity.
Additionally, when studying free radicals in biological systems or when treating various disease conditions caused by free radicals, it is important that the nitrone spin trap have sufficient solubility at the biological site where the free radicals are generated so that the radicals are trapped by the nitrone before they are quenched or cause oxidative damage by their surroundings. Thus, it would be particularly desirable to be able to readily optimize the solubility of nitrone compounds for a particular biological environment ranging in nature, for example, from aqueous to lipophilic.
Accordingly, a need exists for new classes of effective nitrone spin traps having improved properties such as low toxicity and increased solubility in a wide range of biological systems.